Our objectives are to enhance understanding of the mechanisms of Aflatoxin B1 (AFB1) carcinogenesis using the trout model, to determine the effectiveness of putative inhibitors of carcinogenesis in this system, and to more clearly define the limits to which carcinogenesis studies in this model may apply to other animal systems including man. Several enzyme systems for AFB1-DNA adducts will all be determined in hepatocyte preparations of single individuals on control diets, and on diets which included substances (inhibitors) known to affect chemical carcinogenesis in some other animal models. Sufficient individuals will be examined to reveal a) the range of individual variability of these properties in a heterogeneous animal population, b) the range of variability in responsiveness to dietary inhibitors and enzyme inducers and their modes of action, and c) the rate-limiting steps in procarcinogen metabolism which lead to DNA binding or detoxication in this system. These studies will require characterization of the isolated hepatoxyte system for trout. The possible importance of qualitative variations in AFB-DNA adduct profiles between tissues, among individuals, and between resistant and sensitive species will be examined and a preliminary characterization of DNA repair in the trout model will also be carried out. The metabolic fate of aflatoxicol will be determined. These invitro mechanism studies will be accompanied by whole animal tumorigenesis studies to correlate DNA-adduct formation, and factors which affect this process, with AFB1 carcinogenesis. Additional studies are aimed at determining whether dietary inhibition of chemical carcinogenesis can be achieved under biologically relevant doses and exposure patterns. Finally, we propose to investigate the possible genetic basis for individual variability in AFB1 sensitivity in our heterogeneous population of trout, and to initiate a program for developing resistant and sensitive inbred lines for future toxicological studies.